Project 1: Mechanisms of neurotoxicity of lupus anti-NMDAR antibodies: Electrophysiology to Behavior (Huerta PI). The objective of this project is to examine whether key syndromes of neuropsychiatric lupus erythematosus (NPSLE) are caused by autoantibodies that bind the NR2A and NR2B subunits of the N-methyl-o-aspartate receptor (NMDAR). This synaptic receptor is highly expressed in forebrain neurons and is crucially involved in synaptic plasticity, which is regarded as the cellular process underlying memory storage. However, hyperactivity of the NMDAR can trigger excitotoxic effects. Our hypothesis is that certain antibodies function as partial agonists while others function as antagonists for the NMDAR, depending on the mode of interaction with the NR2A and NR2B subunits. Chronic exposure to the anti-NMDAR antibodies would lead to homeostatic imbalance and eventual death of the NMDAR-containing neurons. We aim to determine the toxic potential of a battery of murine and human anti-NMDAR antibodies, the latter having been selected either from a combinatorial library generated from spleen cells of a lupus patient or directly from antigenspecific peripheral blood B cells of three additional patients. We will expand our existing panel by isolating new human, anti-NMDAR antibodies. We will study the mechanisms by which the anti-NMDAR antibodies alter the physiological responses of the NMDAR in neurons of the hippocampus, a brain region critically targeted in NPSLE. Furthermore, we will determine the deleterious effects of the anti-NR2 antibodies over synaptic plasticity in the hippocampus. Finally, we will study the effects of anti-NMDAR antibodies on behaving mice performing a series of cognitive tasks that depend on the integrity of NMDAR-rich brain regions. Thus, we will examine how autoantibodies affect the brain, from the cellular to the behavioral level. Overall, we believe these studies will allow us to determine the functional mechanisms by which the antiNMDAR antibodies cause their neurotoxic effect in the brain. Moreover, we will gain an understanding of the effect of the anti- NMDAR antibodies on the synaptic plasticity processes that underlie memory processing. We foresee that these studies might be relevant for therapeutic protocols in NPSLE.